Various forms and types of disease are known to negatively affect and damage the bones and bone joints of humans and animals. Typically these diseases cause severe and often chronic pain which increases over time eventually progressing to result in loss of function and/or destruction of the joints of the body. The source of this pain and joint damage varies depending upon the disease.
For instance, osteoarthritis is a common degenerative joint disorder which normally affects older persons. Osteoarthritis is marked by inflammation of the joint causing swelling, pain and stiffness reducing the mobility and activity of the patient. These symptoms increase in intensity and regularity with advancing age. The constant inflammation can eventually lead to complete or partial loss of function and damage to the larger weight-bearing joints of the body.
The rheumatic diseases, particularly rheumatoid arthritis, juvenile rheumatoid arthritis and psoriatic arthritis are also marked by chronic inflammation primarily of the synovial tissue leading to pannus formation and eventual destruction of the articular cartilage. In addition to inflammation problems, these diseases also cause the release of various enzymes including collagenase and lysosomal enzymes in the affected area. These enzymes act to indiscriminately destroy extra-cellular collagen fibers and ultimately destroy the connective tissue surrounding the joints.
Another relatively common disease known to affect the bone is metastatic bone cancer which often times accompanies primary cancers in other tissues, notably the lung, breast, and prostate. This form of cancer causes abnormal cell activity in bone, resulting in severe pain and consequent immobility, anorexia, and the need for long-term narcotic analgesia. More specifically, this disease is often associated with overactive osteoblasts (cells which are normally associated with new bone growth) in the bone which cause excessive bone growth in the area of the cancer. Alternatively, the disease may cause abnormally high osteoclastic activity (osteoclasts are cells normally associated with bone resorption) in bone resulting in the destruction of the bone material. Those individuals having excessive osteoclastic activity may also suffer from a condition known as hypercalcaemia caused by excessive levels of calcium ions in the blood resulting from the bone being dissolved or destroyed at an increased rate.
Osteoarthritis, the rheumatic diseases, metastatic bone cancer and other less common forms of inflammatory arthropathies affect great numbers of people in the United States. The cost of treatment and care combined with loss of work time and productivity is incalculable. For instance, it is estimated that one to three percent of the population in the United States is afflicted with rheumatoid arthritis with more than half of these patients suffering inflammation and eventual destruction of the hand and knee joints. With an increasing survival time in the population, these diseases constitute one of the greatest medical, social, and economic problems existing today.
Successful treatment of these diseases generally focuses on pain relief, reduction of inflammation, and preservation of the remaining functional capacity of joints and the adjoining muscles. While complete resolution of the pathological process (e.g. a cure) has not been found, successful early treatment particularly in the case of rheumatoid and osteoarthritis may avert the destructive, deforming phase of the disease.
Presently, the primary method of treating the rheumatoid diseases and arthritis is by drug therapy using anti-inflammatory compounds directed at blocking or reducing synovial inflammation thereby improving function and analgesics directed to reducing pain. Aspirin and other salicylate compounds are frequently used in treatment to interrupt amplification of the inflammatory process and temporarily relieve the pain. Other drug compounds used for these purposes include phenylpropionic acid derivatives such as Ibuprofen and Naproxin, Sulindac, phenyl butazone, corticosteroids, antimalarials such as chloroquine and hydroxychloroquine sulfate, and fenemates. For a thorough review of various drugs utilized in treating rheumatic diseases, reference is made to J. Hosp. Pharm., 36:622 (May 1979).
While these known drug therapies have utility, there are drawbacks to their use. For instance, it may take up to six months of consistent use of some of these medications in order for the product to have effect in relieving the patient's pain. Consequently if the product doesn't work for that particular patient, it could take up to six months before the physician is able to accurately make that assessment. Many of these drugs also cause serious side effects in certain patients, and therefore the patient should be carefully monitored to assure that these side effects are not unduly threatening. Most of these drugs bring only temporary relief to the patient and therefore must be taken consistently on a daily or weekly basis for continued relief. As the disease progresses, the amount of medicant needed to alleviate the pain may increase to relatively high daily doses. The potential for adverse side effects consequently increases with higher dosage amounts. To further complicate matters, many of these patients suffer from other conditions which require them to take a variety of different medications, increasing the risk of negative side effects and interaction between drugs.
Some treatments not only reduce the amount of inflammation and pain, but actually slow the progression of the disease or joint destruction. For instance, gold salts such as gold sodium thiomalate, aurothioglucose, and other sources of auric and aurous ions are said to produce a favorable response in about 75 percent of patients with actual disease remission in 20-25 percent. One major drawback to the use of gold therapy is that the gold is distributed via the blood system not only to the diseased joint, but to a number of tissues in the body including the liver, skin, bone, bone marrow, eyes, and reticuloendothelial system. The gold often causes serious adverse reactions in these tissues including dermatitis, nephrotoxicity, blood dyscrasias and ocular toxicity. A certain amount of the gold also binds with humoral or cellular components such as serum albumin making the bound gold unavailable for purposes of treatment.
Since only a percentage of the total amount of gold administered is actually delivered to the diseased site, significantly high doses of the compound are required for effective treatment. Yet, the risk of adverse reactions is only exacerbated and more pronounced, in certain circumstances becoming life threatening, by virtue of the large dosage amounts administered. It is known to reduce the toxic effects of gold therapy by use of a selenium-containing compound. (U.S. Pat. No. 4,680,286 to Stockel, et al.). However, the amount of gold required for treatment and delivered to the various organs of the body is not reduced using this detoxification method, the selenium is merely provided to expedite elimination of the gold from those organs which can be most severely negatively affected such as the renal system and liver.
A relatively new method of treating rheumatoid arthritis which is also believed to actually slow the progression of the disease is the use of D-penicillamine, a natural metabolite of penicillin. Like many of the other drugs used in the past, penicillamine has drawbacks because it is relatively slow-acting requiring 8-12 weeks of use before it can be determined whether the patient is responding. Penicillamine can also cause several adverse effects and can be toxic in some patients.
Where the inflammation is present in larger joints such as the knee for example, an alternative to drug therapy is the surgical incision of the inflamed synovium using a procedure known as surgical synovectomy. In this procedure the inflamed synovium and pannus formation are surgically removed which tends to relieve the pain and in many cases proves to arrest the disease. In order to avoid the risks of surgery it is also known to destroy the diseased synovium by a procedure known as radiation synovectomy. Radiation synovectomy consist of injecting a radionuclide directly into the articular region affected whereby the radiation kills the diseased tissue to abate the inflamed synovium. Known methods of radiation synovectomy include intra-articular injection of .sup.121 Sn hydroxide in a carrier (See, U.S. Pat. No. 4,906,450 to Lieberman, et al.) and .sup.153 Sm labeled particulate hydroxyapatite (citation).
Radionuclides have also been delivered to the affected area by the use of bone seeking carriers or agents. For instance, the use of .beta.-emitting radionuclides .sup.186 Re and .sup.153 Sm complexed with phosphonates have been suggested for relieving pain in patients with metastatic bone cancer. (See, Coordination Compounds in Nuclear Medicine, Chem. Rev. 1993, 93, 1137-1156, 1148). Phosphonates were initially shown to have a high affinity for sites of actively growing bone when used in skeletal or bone imaging. Di-phosphonate products have also been used for the treatment of various diseases associated with bone joint pain and destruction. For example, 3-amino-1-hydroxypropylidene 1-di-phosphonate commercially available as Pamidronate from Ciba Geigy is known to reduce the pain of abnormal bone turnover known to exist in Paget's Disease (a disease with the symptoms of marked pain and stiffness of bone and joints). Another di-phosphonate product known as Clodronate (di-chloromethane di-phosphonate) and commercially available from Boerhinger has been found to reduce pain and damage in patients having extensive destruction of the lumbar spine. The di-phosphonates have also been used as resorption inhibitors for the treatment of malignant hypercalcaemia associated with overactive osteoclasts. (See Bone Metastases, R. D. Rubins and I. Fogelman, Springer-Verlag London Ltd. 1991).
In a recent study of radionuclide complexes used for radiotherapy in bone tumors, complexes of .sup.117m Sn with the ligands of pyrophosphate, phosphonate, anddiethylene-triaminepentaacetid acid (DTPA) were prepared. The investigators reported that the .sup.117m Sn-DTPA complex was best suited for radiotherapy and that the tin compound itself acted as a bone-localizing agent having a tendency for high bone uptake. See, e.g. Int. J. Nucl. Med. Biol., Vol. 12, No. 3, pp. 167-174 (1985); see also, Radiology, Vol. 186, No. 1 pp. 279-283 (1993).
Thus, the two methods that have primarily been suggested for radiotherapy are articular injection whereby the material is directly injected into the joint for treatment, or i.v. injection whereby the radionuclide complexed with a ligand such as phosphonate is injected intravenously and rapidly localized to the skeleton. While these methods of application attempt to distribute the radionuclide only to the affected area, studies have indicated that activity is leaked or distributed to other parts of the body even when using these techniques. The major drawbacks of these radiotherapeutic agents are the relatively low bone lesion uptake and undesirably high radiation dose to normal tissues. The other problem involved in the preparation of these radiotherapeutic agents is the lack of availability of the radionuclides. Radionuclides are produced from a nuclear reactor or an accelerator Currently there are very few of the radionuclide production facilities operating in the world, which have seriously limited the availability of the medical radionuclides. Furthermore, many radionuclides are either difficult to produce, such as .sup.117m Sn, which can only be produced from a high flux reactor, or too short-lived to be shipped throughout the country, such as .sup.121 Sn (27 hours). As a result, there are very few radiodiagnostic and radiotherapeutic bone agents that have been approved by the United States Food and Drug Administration.
While the rheumatoid diseases, osteoarthritis, metastatic bone cancer and other crippling arthropathies differ somewhat as to source and symptoms, there are certain factors common to each. Firstly, the disease causes chronic or severe pain which significantly impairs the quality of life for the patients. Secondly, the disease, when advanced, causes bone destruction and/or abnormal bone growth. Thirdly, while various forms of drug therapy have been developed for treating these conditions, none have proven successful without continued dosing and/or unwanted side effects. In addition, the drug may be distributed throughout many parts of the body causing toxic side effects in the skin, the liver, the urinary tract and other vital organs. Fourthly, while various forms of radiotreatment have been developed to destroy diseased tissue and/or reduce pain, these treatments involve the use of potentially harmful radioactive materials in the body, are relatively expensive and not easily adapted for convenient use in many doctors' offices or clinics. Thus, there remains a need in the art to develop new methods of treatment to reduce the pain experienced by these patients, and to reduce or prevent joint destruction with minimal negative side effects to the patient.
Thus, a primary object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies which does not require the use of a radionuclide or other radioactive material.
Another object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies wherein the active therapeutic agent is administered to the patient in relatively low dosage amounts.
A further object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies which not only relieves the pain associated with the disease, but also inhibits and/or prevents further destruction of the diseased tissue.
Another object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies wherein the active therapeutic agent is selectively delivered to the bone and bone joints, and specifically to those areas of tissue affected by the disease.
A further object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies wherein single treatments are effective for relatively long term pain relief without the need for daily and/or weekly administration.
A further object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies wherein pain relief and prevention of further tissue damage can be achieved through the administration of small dosage amounts which are effective for extended periods of time.
A further object of the present invention is to provide a composition and method for the palliation of pain in patients with metastatic bone cancer, arthritis, or other inflammatory arthropathies wherein the active therapeutic agent is selectively delivered to the diseased areas providing immediate pain relief as well as relatively long term prevention of tissue destruction by blocking the inflammatory process and/or inhibiting osteoblastic or osteoclastic overactivity.